There are more than 200,000 patients with spinal cord injury in the United States, with about 11,000 new injuries occurring each year. Within this group, about 40 to about 50 percent of these patients have cervical spinal cord lesions resulting in tetraplegia. Patients with low cervical spinal cord lesions with preserved connections to the phrenic nerve motorneuron pools are able to breathe spontaneously without artificial ventilatory assistance. With high cervical cord lesions, however, there is disruption of the bulbospinal respiratory pathways which synapse with inspiratory motorneuron pools, resulting in paralysis of the diaphragm and intercostal muscles, the major muscles of inspiration. With only the accessory muscles of respiration remaining, there is insufficient inspiratory muscle force generating capacity to maintain ventilatory requirements and blood gas homeostasis. Consequently, these patients are generally dependent upon mechanical ventilatory support. Although most patients experience subsequent improvement in neurologic function and are eventually able to breathe spontaneously, about 5 percent of this group will remain dependent upon some form of artificial ventilatory support system for the remainder of their life. Many spinal cord injuries occur in young individuals whose life expectancies have increased substantially due to improvements in medical care. Therefore, many ventilator dependent patients can be expected to live a near normal life span.
While mechanical ventilation maintains basic physiologic needs, most patients experience multiple handicaps. These handicaps include reduced mobility, difficulty with bodily movement, difficulty with speech, significant mental anxiety related to possible disconnection from the ventilator, embarrassment associated with the appearance and sound of the ventilator that attracts attention in social settings, reduced sensation of smell, and atelectasis. Furthermore, mechanical ventilation requires a tracheostomy and is associated with the development of frequent respiratory tract infections often necessitating hospitalization.
In certain spinal cord injuries, the spinal cord below the level of the lesion generally remains intact. The motor pathways in this portion of the spinal cord therefore are amenable to restorative stimulation techniques. Functional electrical stimulation (FES) encompasses a variety of methods to activate motor nerves as a means of restoring function to paralyzed muscles. Bilateral phrenic nerve pacing (PNP), a form of FES, was introduced more than two decades ago. According to this technique, artificial ventilation is produced by rhythmic contraction of the diaphragm such that ventilator dependent tetraplegics can be maintained comfortably without mechanical assist devices. Preserved function of both phrenic nerves is necessary to achieve full-time ventilatory support via PNP. It has been reported that unilateral PNP has a low success rate due to inadequate inspired volume production and therefore PNP is not advised in patients with only unilateral diaphragm function. Obviously, tetraplegics with damage to the phrenic motorneuron pools or phrenic nerves bilaterally are not candidates for PNP.
It is estimated that as many as about 30 to about 40 percent of ventilator dependent tetraplegics have phrenic nerve damage. Conventional PNP techniques require the placement of electrodes directly on the phrenic nerves, carries the risk of phrenic nerve injury and usually requires a thoracotomy, a major surgical procedure with associated risks, required in-patient hospital stay and high cost. PNP may also be accomplished via placement of intramuscular diaphragm electrodes near the phrenic nerve motor point (intramuscular PNP) via laparoscopy, thereby eliminating the need for more invasive thoracotomy and prolonged hospitalization, and therefore significantly reducing cost. This technique essentially eliminates the risk of phrenic nerve injury. This PNP technique also requires preserved bilateral function of the phrenic nerves.
Despite careful pre-surgical screening of patients to ensure phrenic nerve viability, only about 50 percent of patients achieve full-time ventilatory support with either conventional PNP or intramuscular PNP. Nonetheless, PNP is successful in achieving significant ventilator free time (12-15 hours/day) in about 80% of patients. A significant number (10-15%) however achieve <5 hours/day of ventilator free time. The lack of success in achieving full-time support with current PNP technology is usually related to insufficient inspired volume generation. Moreover, even in tetraplegics who have achieved full time support via PNP, insufficient inspired volume generation remains a concern as it often restricts normal speech production.
Several factors may account for inadequate inspired volume production during PNP. First, peripheral nerve electrodes generally do not result in complete diaphragm activation due to the high thresholds of some axons. Second, there is lack of co-incident inspiratory intercostal/accessory (IC) muscle activation, a muscle group which is responsible for the generation of about 35-40% of the vital capacity. The lack of IC activation also prevents the synergistic interaction of combined IC and diaphragm activation to generate inspired volume and airway pressure. In fact, since the rib cage moves paradoxically inward during inspiration, PNP results in the performance of negative work. Finally, PNP is applied with low frequencies (<20 Hz) which converts skeletal muscle from a normally mixed fiber population (e.g. diaphragm is comprised of about 60% slow and about 40% fast fibers) to one comprised predominantly of slow fibers. While low frequency stimulation increases the endurance characteristics of electrically stimulated muscles, it also significantly reduces fiber diameter and maximum force generation. Consequently, the magnitude of maximum inspired volume generation is reduced. Chronic application of PNP with higher stimulus frequencies (>20 Hz) is not possible as this has been shown to result in diaphragm muscle fiber damage.
In patients with inadequate phrenic nerve function, attempts have been made to electrically activate the IC muscle group to provide these patients with an alternative method of pacing. For example, in dog studies it has been shown that the IC muscles can be activated via epidural upper thoracic ventral root stimulation (VRS). VRS results in marked contraction of the IC muscles including the parasternal and interrosseous muscles. Since the expiratory intercostal muscles in the upper portion of the rib cage are very thin, they generate a negligible opposing action. Optimal inspired volumes are generated with ventral electrode placement at the T2 spinal cord level with decreases in inspired volume production at sites above and below this level. Maximal electrical stimulation (6 mA, 50 Hz, 0.1 ms) with a single electrode results in large inspired volumes (about 35% of the vital capacity). In fact, stimulation of the IC muscles by VRS in combination with bilateral phrenic nerve stimulation, results in the generation of inspired volumes that represent about 80% of the inspiratory capacity. Moreover, animals can be ventilated by this method for prolonged time periods (6-8 hours without the development of system fatigue). The mechanism of inspiratory muscle activation by this method occurs via direct spread of current to the motor roots and does not involve stimulation of the spinal cord. Consequently, non-respiratory muscles innervated by the upper thoracic ventral roots are also activated by this technique. Side effects include contraction of the muscles of the upper extremity and trunk.
In clinical trials, this technique was applied in ventilator dependent tetraplegics with absent phrenic nerve function in an attempt to maintain artificial ventilation via IC muscle pacing alone. While VRS resulted in the generation of large inspired volumes (500-900 ml), ventilation could be maintained for only a few hours/day. There are a number of factors which limit the success of this technique. First, the application of chronic low frequency stimulation of the IC muscles reduced their fiber diameter and force generating capacity and, in turn, the magnitude of inspired volume generation. Second, the co-activation of non-respiratory muscles resulted in significant increases in metabolic rate and co-incident increases in ventilatory requirements. Non-respiratory muscle contraction also resulted in mild, but undesirable contraction of the upper extremity and trunk muscles, as seen in the prior animal studies.
In separate clinical trials, VRS was applied in four ventilator dependent patients with only unilateral phrenic nerve function. In these patients, it was demonstrated that artificial ventilation generated by combined IC muscle and unilateral phrenic nerve stimulation was sufficient to comfortably maintain ventilatory support, ranging from 16 hours/day to full-time. Inspired volumes achieved by combined pacing were in the range of that observed with bilateral PNP. This method also resulted in contraction of the upper trunk musculature and mild upper extremity motion, which was generally well tolerated. In some patients however, this movement interfered with certain activities involving fine motor control, such as use of a joystick by mouth control. Another disadvantage of this technique is that it requires two separate procedures for electrode implantation. Given these technical difficulties and the small patient population, this technique is not commercially viable.
Accordingly, current inspiratory muscle pacing techniques have provided many tetraplegics with freedom from mechanical ventilation and in some cases, complete independence. Recent developments have also provided minimally invasive methods of electrode placement for PNP and, potential pacing options for tetraplegics with only unilateral phrenic nerve function. However, these techniques have been successful in achieving full-time ventilatory support in only about 50% of patients. In addition, due to lack of phrenic nerve viability, a substantial number of ventilator dependent tetraplegics cannot be offered any form of pacing. Consequently, the vast majority of ventilator dependent tetraplegics still require the use of mechanical ventilation. The pacing options for ventilator dependent tetraplegics therefore remain quite limited and need to be expanded.